DESCRIPTION: (Applicant's Description) Breast cancer is the second leading cause of cancer death among women. Activation of the estrogen receptor has been shown to be important for the development and growth of many breast cancers. Accordingly, anti-estrogens such as tamoxifen are important therapeutic agents in the treatment and chemoprevention of breast cancers. However, other compounds such as phytoestrogens, fatty amides such as anandamide and retinoid X receptor (RXR) agonists have also demonstrated effectiveness against breast cancer in cell lines and in animal models, but it has been difficult to put all of these compounds together in a common pathway. In vitro, phytoestrogens, estrogen antagonists such as tamoxifen, anandamide and RXR agonists all share the ability to activate a heterodimer of the nuclear receptor RXR and the steroid and xenobiotic receptor (SXR), which implicates SXR as a common molecular target for these compounds. Some breast cancer cell lines express SXR leading to our hypothesis that the protective effect of these diverse compounds is through activation of SXR:RXR. Research carried out under this proposal will investigate SXR as a potential common mechanism by which each of these diverse compounds is active against breast cancer. The relationship between SXR activation and the anti-breast cancer effects of the above compounds will be investigated utilizing breast cancer cell lines as a model system. The in vivo promoter targets of SXR:RXR, and the role of SXR activation in estrogen-dependent versus non-estrogen dependent breast cancers will be studied. The SXR:RXR heterodimer could provide a novel therapeutic target for the development of new anti-breast cancer therapies, and could lead to a basic understanding of the mechanism by which dietary factors such as phytoestrogens are effective in breast cancer prevention.